Granisetron Hydrochloride: Package Insert and Label Information (Page 2 of 2)

PRECAUTIONS

Granisetron hydrochloride is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of granisetron hydrochloride in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.

An adequate QT assessment has not been conducted, but QT prolongation has been reported with granisetron hydrochloride. Therefore, granisetron hydrochloride should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the QT interval are particularly at risk.

Drug Interactions

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro.

In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known.

QT prolongation has been reported with granisetron hydrochloride. Use of granisetron hydrochloride in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may result in clinical consequences.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) (see WARNINGS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24 month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m2 /day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2 /day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m2 , oral) on a body surface area basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2 /day, 20 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m2 /day, 101 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2 /day, 4 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m2 /day, 20 times the recommended human dose based on body surface area) in females. In a 12 month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2 /day, 405 times the recommended human dose based on body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24 month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, granisetron hydrochloride should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).

Granisetron was not mutagenic in in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at oral doses up to 100 mg/kg/day (600 mg/m2 /day, 405 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy

Teratogenic Effects

Pregnancy Category B.

Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m2 /day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2 /day, 255 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when granisetron hydrochloride is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

During clinical trials, 325 patients 65 years of age or older received granisetron hydrochloride tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age.

Adverse Reactions to Granisetron Hydrochloride

QT prolongation has been reported with granisetron hydrochloride (see PRECAUTIONS and Drug Interactions).

Chemotherapy-Induced Nausea and Vomiting

Over 3700 patients have received granisetron hydrochloride tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens. In patients receiving granisetron hydrochloride tablets 1 mg twice a day for 1, 7 or 14 days, or 2 mg daily for 1 day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed inTable 4.

Table 4 Principal Adverse Events in Clinical Trials
Percent of Patients With Event
Granisetron Hydrochloride1 Tablets 1 mg twice a day (n=978) Granisetron Hydrochloride1 Tablets 2 mg once a day (n=1450) Comparator2 (n=599) Placebo (n=185)
Headache 21% 20% 13% 12%
Constipation 18% 14% 16% 8%
Asthenia 14% 18% 10% 4%
Diarrhea 8% 9% 10% 4%
Abdominal pain 6% 4% 6% 3%
Dyspepsia 4% 6% 5% 4%

1 Adverse events were recorded for 7 days when granisetron hydrochloride tablets were given on a single day and for up to 28 days when granisetron hydrochloride tablets were administered for 7 or 14 days.

2 Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine.

Other adverse events reported in clinical trials were:

Gastrointestinal: In single-day dosing studies in which adverse events were collected for 7 days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24 hour efficacy assessment period.

Hepatic: In comparative trials, elevation of AST and ALT (>2 times the upper limit of normal) following the administration of granisetron hydrochloride tablets occurred in 5% and 6% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2%; ALT: 9%).

Cardiovascular: Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and syncope have been observed rarely.

Central Nervous System: Dizziness (5%), insomnia (5%), anxiety (2%), somnolence (1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms has been reported in a patient treated with granisetron hydrochloride tablets.

Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.

Other: Fever (5%). Events often associated with chemotherapy also have been reported: leukopenia (9%), decreased appetite (6%), anemia (4%), alopecia (3%), thrombocytopenia (2%).

Over 5000 patients have received injectable granisetron hydrochloride in clinical trials.

Table 5 gives the comparative frequencies of the five commonly reported adverse events (≥3%) in patients receiving granisetron hydrochloride injection, 40 mcg/kg, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24 hour period following granisetron hydrochloride injection administration.

Table 5 Principal Adverse Events in Clinical Trials — Single-Day Chemotherapy
Percent of Patients with Event
Granisetron Hydrochloride Injection1 40 mcg/kg (n=1268) Comparator2 (n=422)
Headache 14% 6%
Asthenia 5% 6%
Somnolence 4% 15%
Diarrhea 4% 6%
Constipation 3% 3%

1 Adverse events were generally recorded over 7 days post-granisetron hydrochloride injection administration.

2 Metoclopramide/dexamethasone and phenothiazines/dexamethasone.

In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to granisetron hydrochloride, except for headache, which was clearly more frequent than in comparison groups.

Radiation-Induced Nausea and Vomiting

In controlled clinical trials, the adverse events reported by patients receiving granisetron hydrochloride tablets and concurrent radiation were similar to those reported by patients receiving granisetron hydrochloride tablets prior to chemotherapy. The most frequently reported adverse events were diarrhea, asthenia, and constipation. Headache, however, was less prevalent in this patient population.

Postmarketing Experience

QT prolongation has been reported with granisetron hydrochloride (see PRECAUTIONS and Drug Interactions).

OVERDOSAGE

There is no specific treatment for granisetron hydrochloride overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache.

DOSAGE AND ADMINISTRATION

Emetogenic Chemotherapy

The recommended adult dosage of oral granisetron hydrochloride is 2 mg once daily or 1 mg twice daily. In the 2 mg once-daily regimen, two 1 mg tablets are given up to 1 hour before chemotherapy. In the 1 mg twice-daily regimen, the first 1 mg tablet is given up to 1 hour before chemotherapy, and the second tablet, 12 hours after the first. Either regimen is administered only on the day(s) chemotherapy is given. Continued treatment, while not on chemotherapy, has not been found to be useful.

Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients

No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Radiation (Either Total Body Irradiation or Fractionated Abdominal Radiation)

The recommended adult dosage of oral granisetron hydrochloride is 2 mg once daily. Two 1 mg tablets are taken within 1 hour of radiation.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

No dosage adjustment is recommended.

HOW SUPPLIED

White to off-white film coated triangular shaped biconvex tablet debossed with “G1” on one side and plain on the other side.


1 mg Bottle of 20 Tablets: NDC 42043-390-20


1 mg Unit of Use 2s: NDC 42043-390-02

1 mg 20 (2 x 10) Unit Dose Tablets: NDC 42043-390-21 (intended for institutional use only)

Storage

Store between 20° and 25°C (68° and 77°F). [see USP Controlled Room Temperature]. Keep container closed tightly. Protect from light.

PATIENT COUNSELING INFORMATION

Advise patients of the possibility of serotonin syndrome with concomitant use of granisetron and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptomswith or without gastrointestinal symptoms.

Manufactured for : OrchidPharma, Inc.

Princeton, NJ 08540, USA

Manufactured by : Orchid Healthcare

(a division of Orchid Pharma Ltd.)

Irungattukottai — 602 117, India

Revised:11/2018

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

OrchidPharma

NDC 42043-390-20

Granisetron Hydrochloride Tablets, USP

1 mg*

20 Tablets

Rx only

Container Label
(click image for full-size original)

OrchidPharma

20 (2 x 10)

Unit Dose Tablets

NDC 42043-390-21

Granisetron Hydrochloride Tablets, USP

1 mg*

Rx only

* Each tablet contains 1.12 mg granisetron hydrochloride USP equivalent to granisetron, 1 mg.

Intended For Institutional Use Only.

Blister Carton 2s
(click image for full-size original)
GRANISETRON HYDROCHLORIDE granisetron hydrochloride tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42043-390
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
GRANISETRON HYDROCHLORIDE (GRANISETRON) GRANISETRON 1 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE
SODIUM STARCH GLYCOLATE TYPE A POTATO
LACTOSE MONOHYDRATE
HYPROMELLOSE 2910 (3 MPA.S)
MAGNESIUM STEARATE
Product Characteristics
Color white (white to off white) Score no score
Shape TRIANGLE (Triangular Biconvex) Size 7mm
Flavor Imprint Code G1
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:42043-390-02 2 BLISTER PACK in 1 CARTON contains a BLISTER PACK (42043-390-00)
1 NDC:42043-390-00 1 TABLET, FILM COATED in 1 BLISTER PACK This package is contained within the CARTON (42043-390-02)
2 NDC:42043-390-21 2 BLISTER PACK in 1 CARTON contains a BLISTER PACK (42043-390-40)
2 NDC:42043-390-40 10 TABLET, FILM COATED in 1 BLISTER PACK This package is contained within the CARTON (42043-390-21)
3 NDC:42043-390-20 20 TABLET, FILM COATED in 1 BOTTLE, PLASTIC None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078678 04/12/2016
Labeler — OrchidPharma Inc (809429207)
Registrant — Orchid Pharma Ltd (650133507)
Establishment
Name Address ID/FEI Operations
Orchid Healthcare (a division of Orchid Pharma Ltd) 650288850 analysis (42043-390), manufacture (42043-390), pack (42043-390), label (42043-390)

Revised: 01/2022 OrchidPharma Inc

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